Modeling
approaches such as quantitative structure–activity
relationships (QSARs) use molecular descriptors to predict the bioavailable
properties of a compound in biota. However, these models have mainly
been derived based on empirical data for lipophilic neutral compounds
and may not predict the uptake of ionizable compounds. The majority
of pharmaceuticals are ionizable, and freshwaters can have a range
of pH values that affect speciation. In this study, we assessed the
uptake of 10 pharmaceuticals (acetazolamide, beclomethasone, carbamazepine,
diclofenac, gemfibrozil, ibuprofen, ketoprofen, norethindrone, propranolol,
and warfarin) with differing modes of action and physicochemical properties
(p<i>K</i><sub>a</sub>, log <i>S</i>, log <i>D</i>, log <i>K</i><sub>ow</sub>, molecular weight
(MW), and polar surface area (PSA)) by an in vitro primary fish gill
cell culture system (FIGCS) for 24 h in artificial freshwater. Principal
component analysis (PCA) and partial least-squares (PLS) regression
was used to determine the molecular descriptors that influence the
uptake rates. Ionizable drugs were taken up by FIGCS; a strong positive
correlation was observed between log <i>S</i> and the uptake
rate, and a negative correlation was observed between p<i>K</i><sub>a</sub>, log <i>D</i>, and MW and the uptake rate.
This approach shows that models can be derived on the basis of the
physicochemical properties of pharmaceuticals and the use of an in
vitro gill system to predict the uptake of other compounds. There
is a need for a robust and validated model for gill uptake that could
be used in a tiered risk assessment to prioritize compounds for experimental
testing
